This invention relates generally to syringe systems that are suitable for packaging, mixing and delivering a medical solution formed by mixing a dry, lyophilized drug component with a liquid diluent. More specifically, the invention relates to syringe systems that permit lyophilization of a drug solution contained therein. The invention also relates to methods of making such syringe systems.
Generally, lyophilization is a process by which the volatile components, such as solvents including water, are removed from a substance. Certain substances, especially pharmaceutical substances, are more stable over time if the volatile components are removed. Since lyophilized drugs are typically more stable, have longer shelf life, have more reliable purity and are easier to store and transport than other formulations, lyophilization has become commonplace in the pharmaceutical industry.
It is known to provide xe2x80x9cwet/dryxe2x80x9d drug mixing and delivery products that utilize a primary syringe system, containing a lyophilized drug, and a secondary syringe system that contains a diluent used to reconstitute the lyophilized drug. When the drug is to be administered to a patient, the secondary syringe system is inserted into the primary syringe system and the diluent is dispensed into the primary syringe barrel to reconstitute the lyophilized drug. These xe2x80x9cwet/dryxe2x80x9d syringe systems are useful in pharmaceutical applications where pre-mixed solutions or suspensions of a drug are not stable enough to withstand prolonged periods of storage. Such systems are disclosed in U.S. Pat. No. 5,779,668, the subject matter and entire writing of which is incorporated herein by reference.
Typically, the manufacture of the primary syringe system containing the lyophilized drug involves mass processing of a number of syringe systems in a lyophilization chamber. Prior art lyophilization chambers are exemplified by FIG. 1 and U.S. Pat. No. 4,506,455, the subject matter and entire writing of which is incorporated herein by reference. The lyophilization chamber 10 generally comprises a chamber wall 12 which is manufactured to provide insulation during the lyophilization process. Enclosed within the wall 12 are a series of shelves 14 which are adapted to move relative to one another and which include implements, such as refrigeration and heating coils, for raising and lowering the temperature of the shelves. A hydraulic actuator 18 moves the top shelf upward, creating a space between the top shelf and the adjacent second shelf, and a number of syringe systems 22, supported on trays or xe2x80x9cpucksxe2x80x9d 20 are loaded onto the second shelf. The containers or trays 20 are typically transported on a transport carriage 26 and slid across a loading table 24 such that the trays can be loaded onto the respective shelves 14. The top shelf and second shelf are then raised and syringe systems 22 are loaded onto the third shelf. This loading sequence is repeated until the upright syringe systems 22 occupy the spaces between the shelves 14. Once fully loaded, the chamber door 19 is closed and the interior subjected to a lyophilization process which may typically take a number of days to complete. After the lyophilization process is complete, the top shelf is lowered and the shelves are collapsed towards one another such that movement of the shelves causes a collapse and therefore sealing of the syringe systems 22 in a manner that will be described below.
Typical lyophilization processes involve two stages. In the first stage, the drug solution is subjected to low temperatures, typically xe2x88x9250 (C) and completely frozen to separate the water or other solvent from the solute ingredients. In the second stage, the water or other solvent is separated from the frozen product by heating the contents slowly, under carefully controlled conditions, and under high vacuum so that the solvent leaves the products through sublimation. Drying is accomplished as the frozen solvent is transformed into vapor. This vapor migrates through the crystallized drug and escapes from the syringe system through a venting system.
FIGS. 2 and 3 illustrate a prior art syringe system for permitting venting of the drug during lyophilization. During the lyophilization process, the syringe system 30 is maintained in an upright position in a metal holder or puck (not shown). FIG. 2 illustrates the syringe system 30 configured in a venting position. The syringe system 30 comprises a generally cylindrical syringe barrel 32 which includes an open end 33 and a closed end 34. The closed end 34 includes a delivery passage 36 which is later used for delivery of the mixed drug from the syringe system 30. During lyophilization, the delivery passage 36 is sealed by a closure 37 and the syringe barrel 32 contains a drug solution 35.
In accordance with prior art syringe systems, venting is provided by a series of venting channels 39 which are formed in the syringe barrel 32 near the open end 33. These channels are formed between a series of ribs 37 that are integrally molded with the syringe barrel 32. The syringe system 30 also includes a sterility maintenance sleeve 42 and plug cap 56 which are intended to seal the interior of the syringe barrel 32 against contamination once the syringe is moved into its sealed position as shown in FIG. 3. The sterility maintenance sleeve 42 includes a large diameter portion 52 from which extends a stopper retaining head 50 that is shaped to resiliently retain a rubber stopper 44 thereon. Stopper 44 is adapted to sealingly engage the interior surface of the syringe 32 and, in the venting position as shown in FIG. 2, abuts the ribs 37 thereby permitting egress of vapor through the channels 39 from the drug chamber 45 of the syringe 32.
FIG. 3 illustrates the syringe system 30 configured in a sealing position after the lyophilization process has been performed. The sterility maintenance sleeve 42 and plug cap 56 are moved to the sealing position in which the stopper 44 is located further into the syringe 32 and a sealing head 57 of the plug cap 56 engages the syringe 32. As will be recognized by those of ordinary skill in the art, the plug cap and sterility maintenance sleeve 42 are moved to the sealing position from the venting position by movement of the shelves in the lyophilization chamber.
Prior art syringe systems require a rather extensive vertical travel of the sealing components when moving from a venting position to a sealing position. This travel dimension places limits on the capacity of the lyophilization chamber since the shelves must be spaced to accommodate the syringe system when it is configured in the venting position. Since lyophilization processes may take several days for some pharmaceutical substances, space within the lyophilization chamberxe2x80x94typically a very expensive piece of equipmentxe2x80x94is at a premium. It would therefore be desirable to provide a syringe system which requires less vertical movement for sealing compared to prior art syringe systems. Such a system would permit more efficient use of the space within the lyophilization chamber.
The venting techniques of prior art syringe systems are also disadvantageous in that they do not provide an efficient flow path for drug solution vapor during the drying steps of lyophilization. More specifically, the fluid path that vapor must travel to escape from the drug chamber to the ambient surroundings during lyophilization is somewhat restricted, since the venting passages are formed by the engagement of a resilient stopper with channels formed in the syringe barrel. It would therefore be desirable to provide a syringe system which provides an efficient flow path for drug solution vapors during lyophilization, thereby decreasing the time required for drying during lyophilization.
The benefits and advantages described above are realized by the present invention which provides a syringe system that requires a decreased vertical travel when changing from a venting configuration to sealing configuration. In a preferred embodiment, the invention provides a syringe system including a syringe barrel having an open end and an opposite dispensing end, a sterility maintenance sleeve cooperating with the syringe barrel and including a sleeve barrel having an interior space, a stopper affixed thereto for sealingly engaging the syringe barrel to define a drug chamber for containing drug solution, and a venting passage formed in the sterility maintenance sleeve and the stopper in order to permit egress of drug solution vapor from the drug chamber during the lyophilization process. A plug cap is cooperatively associated with the sterility maintenance sleeve and provided with an occluding tip for sealing the venting passage. The sterility maintenance sleeve may be initially inserted to an installed position, where the stopper is disposed further into the syringe barrel compared to prior art devices and thus the overall height of the syringe system in the venting configuration is reduced.
The occluding tip is preferably configured to permit adequate flow of vapor through the venting passage for efficient drying during the lyophilization process. Specifically, the occluding tip is provided with a tapered end which is dimensioned so as to provide an annular flow passage with the venting passage formed in the sterility maintenance sleeve. The occluding tip is adapted to occupy, in the venting position, an enlarged diameter portion of the venting passage, for example, a female threaded portion for later receiving a male threaded portion of a diluent syringe. The shape of the flow passage for vapors from the drug solution is therefore less restrictive than prior art devices and thus provides for more efficient and quicker lyophilization.
The plug cap is preferably provided with a support structure in the form of flexible fins that extend outward from a central portion. The fins function to frictionally engage an interior surface of the sterility maintenance sleeve to support the plug cap in the venting position. The fins are flexible enough to deform and thereby permit the plug cap to move within the sterility maintenance sleeve upon application of a force to the plug cap without causing movement of the sterility maintenance sleeve within the syringe barrel. The fins also provide, in conjunction with the interior surface of the sterility maintenance sleeve, large flow passages for drug solution vapor, thereby providing for more efficient drying and vapor egress from the drug chamber during lyophilization.
Numerous other advantages and features of the present invention will become readily apparent from the following detailed description of the invention, from the claims, and from the accompanying drawings.